Ligand binding in the catalytic antibody 17E8. A free energy perturbation calculation study

We present free energy calculations on the Michaelis complexes of the catalytic antibody 17E8 with two substrates, which differ only in their side chains. Replacing a -CH₂- group with a -S- increases K(M) by a factor of about 5-8. This corresponds to a free energy 'preference' for the -CH₂- ligand of about 0.9-1.3 kcal/mol. The calculations semiquantitatively reproduce the experimental free energies and show that the preference for a -CH₂- over a -S- is mainly due to the more favorable solvation free energy in the unbound form of the molecule.